taat06i2p24

Trends Biomater. Artif. Organs, Vol 20(1), pp 24-30
(2006)and G.Buvaneswari*
24
M.Srinivas
http://www.sbaoi.org
A Study of in Vitro Drug Release from Zirconia Ceramics
M. Srinivas and G. Buvaneswari*
Department of Chemistry,
VIT, Deemed University, Vellore 14
*corresponding author
In the field of biomedical applications, Zirconia is an important biomaterial due to its excellent biocompatibility and
high mechanical strength. Block forms of such bio inert ceramics can be used as defect bone filler. Designing such
implants associated with therapeutic agents like antibiotics, anti-inflammatory etc. exhibiting targeted drug delivery
with controlled release profile is a challenge. In the present work, an in vitro drug release of two drug loaded forms
(punched pellet and alginate beads) of the zirconia and yttria stabilized zirconia is studied. The ceramics are
synthesized by combustion method. The model drugs selected are the antibacterial drug, ciprofloxacin hydrochloride
(CFH) and anti-inflammatory drug, diclofenac sodium (DFS).
Introduction
Ceramics are increasingly used for biomedical
applications in recent years. The ceramics that
are used in implantation and clinical purposes
included alumina, partially stabilized zirconia
(PSZ), bio-glass, glass ceramics, calcium
phosphates (HAP, β- TCP) and crystalline or
glassy forms of carbon and its compounds [1,2].
Zirconia is a biomaterial that has advantages over
other ceramics because of its high mechanical
strength and fracture toughness. Yttrium Oxide
partially stabilized Zirconia belongs to a new class
of ceramics exhibiting an improved toughness
when compared to alumina. Zirconia shows
different crystal structures at different
temperatures such as at 1000-1100°C it shows
tetragonal structure and cubic phase at around
2000°C. Yttrium Oxide(Y 2O 3) stabilizes the
tetragonal phase, so that, upon cooling, the
tetragonal crystals made of ZrO2-Y2O3, can be
maintained in meta stable state and not transforms
in a monoclinic structure [3]. Todays main
application of Zirconia ceramics is THR ball heads
[4].
Yoshiki et al., studied the wear of Yttria stabilized
Zirconia in the femoral head. [5]. The strength
and reliability of surface treated Yttria stabilized
Zirconia dental ceramics has been studied by
Toma Kosma et al.[6].
Though zirconia (ZrO 2) and Yttria stabilized
Zirconia(Y-ZrO2) have wider applications such
as hip and knee prostheses, hip joint heads,
temporary supports, tibial plates, dental
crowns, not much literature reports are
available on the studies of this oxide ceramics
as drug carriers. Present work aims to study
the in vitro drug release using the above
mentioned oxide bioceramics as carriers. The
model drugs selected are Ciprofloxacin HCl
(CFH) and Diclofenac Sodium (DFS).
Materials And Methodology
Materials
Zirconyl Nitrate ZrO(NO 3)2.XH 2O (98%, CDH
Chemicals, India), Yttrium Oxide Y2O3 (98%,CDH
Chemicals, India), Urea (SD Fine Chemicals,
India), Sodium Alginate (SD Fine Chemicals,
India), Calcium Chloride (SD Fine Chemicals,
India), Ciprofloxacin HCl and Diclofenac Sodium
were obtained from Aurobindo Pharm Ltd,
Hyderabad, India.
A Study Of In Vitro Drug Release From Zirconia Ceramics
Instruments
Veego USP Dissolution Apparatus, FTIR
(Thermonicolet 330), XRD (Philips), High
temperature
muffle
Furnace,
UV
Spectrophotometer (Schimadzu 1601),
Viscotester 550, Monsanto Hardness tester.
Synthesis of Zirconia
The synthesis of ZrO2 involves two steps. In the
first step the precursors were prepared by self
sustaining combustion technique using urea as a
fuel. In the second step the precursors were
heated at elevated temperatures in order to get
pure crystalline materials. The procedure for
synthesis of the above mentioned materials are
given below. The required amount of Zirconyl
Nitrate was dissolved in minimum quantity of
distilled water. To the solution appropriate amount
of urea was added and mixed thoroughly. The
mixture was heated using an electrical Bunsen
burner. The clear solution was evaporated. The
voluminous mass obtained was ground well. The
precursor thus obtained was heated at 700°C for
3hrs.
Synthesis of Yttria Stabilized Zirconia
The required amount of Zirconyl Nitrate was
dissolved in minimum quantity of distilled water.
Specified amount of Yttrium oxide was dissolved
in 1:1 Nitric acid, this solution mixed with Zirconyl
nitrate solution. To the solution appropriate amount
of urea was added and mixed thoroughly. The
mixture was heated using an electrical Bunsen
burner. The clear solution was evaporated. The
voluminous mass obtained was ground well. The
precursor thus obtained was heated at 700°C for
6hrs and 1050°C for 12hrs.
Preparation of Pellets by Punching Method
Drug loaded implants were prepared by taking
Drug and carrier at 1:2 ratio (weight ratio). A
homogeneous blend was made by thorough
mixing for about 10-20 minutes using pestle and
mortar. To improve the compaction properties the
above mixture was granulated using gelatin as a
binding agent. To the mixture 3-5 drops of 5%
gelatin solution were added and a paste was
obtained. The paste was dried in a hot air oven at
70°C for 1hr. The dried mass was ground and the
powder was punched into pellets (8mm
diameter and 3mm thick) by applying a pressure
25
of 4 Kg/cm2. The pellets obtained were used for
dissolution studies.
Preparation of Drug Loaded Alginate Beads
Drug loaded alginate beads were prepared by
extruding a solution of sodium alginate (2.5%W/
V) containing 1% drug through a syringe into a
solution of calcium chloride (2.5%W/V) of known
concentration. The viscosity of the drug containing
sodium alginate gel was determined at room
temperature. The equipment VISCOTESTER VT
550 was used. After 5 minutes of contact time,
the beads were filtered and air-dried. The excess
of calcium chloride adhering to the surface of the
beads was removed by washing with water
followed by air-drying overnight. The average bead
size was measured as 2.5mm with an accuracy
of around ± 0.001mm. Similarly drug and ceramic
loaded alginate beads were also prepared.
In Vitro Drug Release From Pellets
The pellet containing the carrier and drug was
placed in the basket of USP Dissolution apparatus.
The in vitro release of Ciprofloxacin HCl and
Diclofenac Sodium from pellets was carried out
at 37°C in dissolution medium (deionized water)
using USP Dissoultion Apparatus with 900 ml of
dissolution medium. The release medium was
collected at regular time intervals for 8hrs and
replaced with a fresh medium (2ml) each time.
The amount of Ciprofloxacin and Diclofenac
Sodium released was measured at λmax of 271
and 276 nm respectively using Shimadzu UV 1601
spectrophotometer. The experiments were carried
out in duplicate.
In Vitro Drug Release from Alginate Beads
The drug loaded alginate beads were taken in a
pouch and placed in the basket of USP Dissolution
apparatus. The in vitro release of the drug
Ciprofloxacin and Diclofenac Sodium from the
beads was carried out at 37°C in dissolution
medium (deionized water) using USP Dissoultion
Apparatus with 900 ml of dissolution medium. The
release medium was collected at regular time
intervals for 8hrs and replaced with a fresh medium
(2ml) each time. The amount of Ciprofloxacin and
Diclofenac Sodium released was measured at
λ max of 271 and 276 nm respectively using
Shimadzu UV 1601 spectrophotometer. The
experiments were carried out in duplicate.
26
M.Srinivas and G.Buvaneswari*
Similar experiments were carried out for drug
and ceramic loaded alginate beads also.
The compounds were analyzed by powder Xray diffraction (Phillips, CuK α) at room
temperature for phase purity. The FT-IR spectra
(Thermonicolet- 330) were recorded in the range
2000-4000 cm-1 using KBr technique.
% C u m u m a la ti v e r e le a s
Characterization
Z ir c o n ia + C F H ( P e lle t)
120
100
80
60
40
20
0
Results And Discussion
The Zirconia and yttria stabilized Zirconia was
prepared by combustion method using urea-nitrate
mixture. This method is choosen because self
sustaining combustion process is rapid and leads
to direct conversion from the molecular mixture
of the precursor solution to the final oxide products.
From the powder X-ray diffraction it is observed
that tha two oxide ceramics are pure and
crystalline. The lattice parameters are in
agreement with the reported values. In the present
work zirconia as well as 4 mol % hyttria stabilized
zirconia crystallize in tetragonal system with the
cell parameters a = 4.74 Å , c = 12.91 Å and a =
5.12 Å, c = 5.91Å respectively.
Study of In vitro drug release
The ceramic implants are prepared by two
methods. In one method, the drug loaded ceramic
mixture is compressed into pellets using gelatin
(7) as a binder. In the other method, drug loaded
ceramic containing alginate (8) beads are
prepared. Alginate bead method is chosen by
assuming that it would provide controlled and
targeted release of the drugs.
In vitro release of drugs from compacted
pellets
The dissolution experiment using CFH and DFS
mixed Zirconia pellets was carried out at 37°C in
deionized water medium independently. In the
case of CFH mixed ceramic pellet, nearly 65.9%
of the drug was released within 30 minutes. After
60 minutes nearly 98.6% of the drug was released.
Around 99% of the drug has been released at 150
minutes. After 180 minutes the pellet was
completely disintegrated. The CFH release pattern
from ZrO2 pellet is shown in Fig 1.
100
200
300
T im e (m in s )
Fig1. The CFH release pattern from Zirconia + CFH
Pellet
Similarly from DFS mixed zirconia pellet, nearly
64.4% of the drug was released within 30 minutes.
After 60 minutes nearly 97.9% of the drug was
released. Around 99% of the drug has been
released at 120 minutes. After 150 minutes the
pellet was completely disintegrated. The DFS
release pattern from ZrO 2 pellets is shown
in Fig 2.
Z irc o n ia + D F S (P e lle t)
% C u m u la t iv e r e le a s e
Synthesis and Characterization of ZrO 2
and Y-ZrO2
0
120
100
80
60
40
20
0
0
50
100
15 0
T im e (m in s )
Fig 2. The DFS release pattern from Zirconia + DFS
Pellet
The dissolution study of CFH added yttria
stabilized zirconia pellet indicates that nearly
58.6% of the drug was released within 30
minutes. After 60 minutes nearly 95.4% of the
drug was released. Around 99% of the drug has
been released at 120 minutes. After 150 minutes
the pellet was completely disintegrated. The CFH
release pattern from YZrO2 pellet is shown in
Fig 3.
A Study Of In Vitro Drug Release From Zirconia Ceramics
27
% C u m u la t iv e re le a s e
YZrO 2 + C F H (P e lle t)
120
100
80
60
40
20
0
0
50
10 0
1 50
Tim e (m in s )
Fig 3. The CFH release pattern from Y-ZrO2 + CFH
Pellet
Fig 5. IR spectrum of Zirconia + Ciprofloxacin
loaded pellets(1A: Zirconia ;1B: Zirconia +
Ciprofloxacin; 1C: Ciprofloxacin)
The DFS mixed yttria stabilized zirconia pellet
showed a release of nearly 42.6% of the drug within
30 minutes. After 60 minutes nearly 60.9% of the
drug was released. Around 96% of the drug has
been released at 210 minutes. After 240 minutes
the pellet was completely disintegrated. The DFS
release pattern from YZrO2 pellet is shown in
Fig 4.
Y Z r O 2 + D F S ( P e ll e t )
% C u m u la t iv e r e le
120
100
Fig 6 IR spectrum of Zirconia + Diclofenac sodium
loaded Pellets( 2A: Zirconia ; 2B: Zirconia +
Diclofenac Sodium ; 2C: Diclofenac Sodium)
80
60
40
20
0
0
50
100
150
200
250
T im e ( m in s )
Fig 4. The DFS release pattern from YZrO2 + DFS
Pellet
The release behavior of the drug could be
influenced by the method of synthesis of the
ceramic (both zirconia and yttria stabilized zirconia)
which decides the particle size and by the nature
of drug and ceramic binding strength. The fast
release observed in the present study indicates
poor binding between the drug and the ceramics
The absence of chemical interaction between the
drug and the carrier is visible from FT-IR
spectrum (Figs. 5-8).
Fig 7 - IR spectrum of Yttria stabilized zirconia +
Ciprofloxacin HCl Pellets (5A: Yttria stabilized Zirconia ; 5B: Yttria stabilized Zirconia + Ciprofloxacin
HCl Pellets ; 5C: Ciprofloxacin HCl)
28
M.Srinivas and G.Buvaneswari*
C F H lo a d e d b e a d s
% C u m u l a ti v e r e l e
1 20
1 00
80
60
40
20
0
0
1 00
2 00
30 0
40 0
50 0
T i m e (m i n s )
The percentage cumulative release profiles of
both the drugs CFH and DFS (Figs 1 2, 3, 4)
indicate that the diffusion of the drugs from the
respective compacted pellets follows the same
mechanism.
In vitro release of drugs from alginate beads
The dissolution experiment using drug loaded
alginate beads were carried out initially. The
results were compared with the drug release
from drug loaded ceramic containing alginate
beads. Nearly 60.9% of the CFH drug was
released within 60 minutes. After 180 minutes
nearly 88.5% of the drug was released. Around
96% of the drug has been released at 420
minutes. The CFH release pattern from alginate
beads is shown in Fig 9.
About 28.4% of the DFS drug was released within
60 minutes. After 180 minutes nearly 42.4% of
the drug was released. Around 71.1% of the drug
has been released at 420 minutes. The DFS
release pattern from beads is shown in Fig 10.
In vitro release of drugs from (ZrO2 + drug)
loaded Alginate beads
D F S lo a d e d a lg in a te b e a d s
80
% C u m u l a ti v e r e l e a s
The results obtained in this study show that
diluting the drug using ZrO2 (1:2 weight ratio)
extends the drug release for 150 minutes in the
case of both CFH and DFS. Similarly, diluting
the drug using YZrO2 (1:2 weight ratio) extends
the drug release for 150 minutes in the case
CFH loaded pellets and for DFS loaded pellets
drug release is extended for 240 minutes.
Fig 9. The CFH release pattern from alginate beads
70
60
50
40
30
20
10
0
0
1 00
20 0
300
4 00
50 0
T i m e (m i n s )
Fig 10. The DFS release pattern from Alginate beads
below. Nearly 37.3% of CFH drug was released
within 60 minutes. After 180 minutes nearly
64.9% of the drug was released. Around 94.9%
of the drug has been released at 420 minutes.
The CFH release pattern from ZrO 2 + CFH
loaded alginate beads are shown in Fig 11.
ZrO 2 + C F H lo a d ed b ea d s
100
90
% C um u lative relea se
Fig 8. IR spectrum of Yttria stabilized Zirconia +
Diclofenac Sodium Pellets (6A: Yttria stabilized
Zirconia ; 6B: Yttria stabilized Zirconia + Diclofenac
Sodium Pellets; 6C: Diclofenac Sodium)
80
70
60
50
40
30
20
10
0
0
10 0
200
300
4 00
5 00
T ime (min s)
The results obtained when the dissolution
experiments were carried out using drug loaded
ceramic containing alginate beads are given
Fig 11. The CFH release pattern from ZrO2 + CFH
loaded Alginate beads
A Study Of In Vitro Drug Release From Zirconia Ceramics
Nearly 25.8% of DFS drug was released within
60 minutes. After 180 minutes nearly 59.8% of
the drug was released. Around 97.8% of the drug
has been released at 420 minutes. The DFS
release pattern from ZrO2 + DFS loaded alginate
beads are shown in Fig 12.
ZrO 2 + D F S lo a d e d b e ad s
% C um u lative relea se
120
100
80
60
40
20
0
0
100
200
300
400
500
T ime (min s)
Fig 12. The DFS release pattern from ZrO2 + DFS
loaded Alginate beads
In vitro release of drugs from (YZrO2 + drug)
loaded Alginate beads
When drug containing yttria stabilized zirconia
ceramic loaded alginate beads were subjected
to dissolution experiments, nearly 62.8 % of CFH
drug was released within 60 minutes. After 180
minutes nearly 85.1% of the drug was released.
Around 97.4% of the drug has been released at
420 minutes. The CFH release pattern from
YZrO2 + CFH loaded alginate beads are shown
in Fig 13.
Similarly, about 41.7% of DFS drug was released
within 60 minutes. After 180 minutes nearly 53.5%
of the drug was released. Around 86.5% of the drug
has been released at 420 minutesThe DFS release
pattern from YZrO2 + DFS loaded alginate beads
are shown in Fig 14. In all alginate bead experiments
it is observed that the swollen beads maintained
their shape even after 480 minutes.
The results obtained in this study indicate that the
drug release is slow when compared with the
29
release of drugs from compacted pellets. In the
case of alginate beads the drug release period
extends to more than 8 hrs. When the ceramic
and the drug mixed Sodium alginate is extruded
into a solution of calcium chloride, the soluble
alginate is cross-linked with calcium chloride.
As a result the drug and the ceramic embedded
in insoluble calcium alginate gel forms. The
formation of calcium alginate reduced the
permeability of the drug particles and thus delays
the release of the embodied drug. It is observed
that the percentage of drug release from alginate
beads encapsulating the ceramic and the drug
is not significantly different from the beads
containing the drug only. Similar observation was
encountered by Ribeiro et al (9), when they
studied calcium phosphate - aliginate
microspheres as enzyme delivery matrices. This
could be due to the fact that the drug does neither
make physical nor chemical interaction with the
embodied ceramic particles (Figs 5-8). The
weak binding between the drug and ceramic is
illustrated by the experiment carried out using
compacted pellets of the drug and the carrier
mixture. The Infrared spectral studies on the drug
loaded ceramic containing algiante beads also
indicate that there are no chemical interactions
between the drug, alpha alumina ceramics and
the alginate frame work.
Conclusions
The present work investigates the invitro drug
release using zirconia and 4 mol% yttria
stabilized zirconia drug carriers. The percentage
drug release extends for 5 hrs in the case of
both ZrO2 and YZrO2 pellets. The drug release
profiles indicate that the mechanism of drug
release may be the same except for DFH mixed
YZrO2 pellet. On the other hand, ther percentage
drug release extends for more than 8 hrs in the
case of alginate beads and the mechanism of
drug release may be different with respect to the
oxides as well as the drugs.
Acknowledgements
The authors thank VIT for providing all required
facilities to carry out the experiments.
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M.Srinivas and G.Buvaneswari*
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International Conference on
Design of Biomaterials
BIND-06
&
XVII Annual Conference of SBAOI
December 8-11, 2006
at
Indian Institute of Technology, Kanpur
http://www.iitk.ac.in/infocell/announce/bind06
E-mail: [email protected]